The present invention relates to a method and a device for measuring the concentration of urea or a similar substance in a composite solution. The concentration of urea is difficult to measure directly, and therefore, urea is catalytically decomposed by urease and the differential conductivity is measured.
The solution is preferably a medical solution but can also be a biological solution such as plasma. The present invention relates particularly to the measurement of the concentration of urea in connection with dialysis.
The present invention is based on the technique which is disclosed in European Patent No. 0,437,789. This patent discloses, for example, a system for measuring the urea concentration in a complex solution by decomposing urea into ammonium ions catalyzed by urease. It is difficult to measure the urea directly, and it must, therefore, first be converted into ammonium ions. The change in the conductivity due to the contribution of the ammonium ions is measured by means of a conductivity meter.
In German Patent No. 39 00 119 a urea sensor of a similar type is described. A capillary is positioned in a tube, through which blood passes. By means of the capillary, plasma is drawn out of the blood and is allowed to pass through a urease column. The difference in conductivity before and after the urease column is measured and the difference is correlated to the urea content. In order to keep the temperature constant in the measuring apparatus the dialysis fluid is circulated in a closed loop around the urease column and the two conductivity measurement cells.
Japanese Patent No. 60-165551 discloses a similar arrangement, where an ion exchange column is used to remove electrolytes by means of anion-cation-exchange. In this way, the accuracy of the measured values are considerably improved, since the relative change in the conductivity becomes larger due to the fact that the initial conductivity is lower or almost zero. Furthermore, a buffer is added.
U.S. Pat. No. 3,930,957 describes a urea sensor, where an organic buffer solution is added. As an example a solution of 0.05M Tris(hydroxymethyl)aminomethane can be used, which is adjusted to a pH-value of about 6-7 by the addition of glycine.
In accordance with the present invention, a method and apparatus for measuring the concentration of urea or similar substance in composite solutions is provided. According to the method of the present invention, a method for measuring the concentration of a decomposable compound in a solution has been discovered, comprising adding a buffer in gaseous form to the solution, measuring the conductivity of the solution, decomposing the decomposable compound so as to produce a reacted solution, measuring the conductivity of the reacted solution, and calculating the differential conductivities between the solution and the reacted solution so as to provide a measure of the concentration of the decomposable compound in the solution.
In a preferred embodiment, the buffer in gaseous form comprises carbon dioxide. Preferably, the decomposable compound comprises urea. More preferably, the solution comprises biocarbonate ions. In a preferred embodiment, the decomposing of the decomposable compound comprises catalytically reacting the solution and preferably with urease.
In accordance with one embodiment of the method of the present invention, the adding of the carbon dioxide to the solution comprises diffusing the carbon dioxide through a silicon tube into the solution.
In accordance with another embodiment of the method of the present invention, calculating of the differential conductivities comprises increasing the pressure of the solution in order to increase the solubility of the carbon dioxide in the solution. Preferably, the pressure is increased to about 0.1 MPa.
In accordance with another embodiment of the method of the present invention, calculating of the differential conductivities comprises decreasing the temperature of the solution in order to increase the solubility of the carbon dioxide in the solution. Preferably, the temperature is decreased to about 25xc2x0 C.
In accordance with another embodiment of the method of the present invention, measuring of the conductivity of the solution and measuring of the conductivity of the reacted solution is carried out by means of a single measurement cell. In a preferred embodiment, the method includes measuring the conductivity of the solution by connecting the single measurement cell at a location upstream of the decomposing step and measuring the conductivity of the reacted solution by connecting the single measurement cell at a location downstream of the decomposing step.
In accordance with another embodiment of the method of the present invention, the method includes measuring the conductivity of the solution by diverting a portion of the solution from the decomposing step.
In accordance with another embodiment of the method of the present invention, the method includes diverting a portion of the solution into a flow path separate from the decomposing step, measuring the conductivity of the solution by means of a first measurement cell in the separate flow path, and measuring the conductivity of the reacted solution by means of a second measurement cell downstream of the decomposing step. In a preferred embodiment, the method includes delaying the flow of the method through the separate flow path whereby the flow of the solution through the separate flow path to the first measurement cell and the flow of the reacted solution to the second measurement cell can take approximately the same amount of time.
In accordance with another embodiment of the method of the present invention, a method is provided for measuring the concentration of a decomposable compound in a solution comprising dividing the solution into a first portion and a second portion, decomposing the decomposable compound in the first portion of the solution so as to provide a first reacted solution, equalizing the temperatures of the first reacted solution and the second portion of the solution in a heat exchanger having a mean temperature, measuring the conductivities of the temperature equalized first reacted solution and second portion of the solution, and calculating the differential conductivity between the first reacted solution and the second portion of the solution, temperature compensating the differential conductivity by means of the mean temperature of a heat exchanger, and calculating the concentration of the decomposable compound from the compensated differential conductivity. Preferably, the decomposable compound comprises urea. In a preferred embodiment, decomposing of the decomposable compound comprising catalytically reacting the decomposable compound in the solution, and preferably catalytically reacting the solution comprises reaction with urease.
In accordance with another embodiment of the method of the present invention, the measuring of the conductivities comprises measuring the conductivity of the temperature equalized first reacted solution and the second portion of the solution with separate conductivity measurement cells.
In accordance with another embodiment of the method of the present invention, the heat exchanger comprises a heat exchange fluid in heat exchange communication with the first reacted solution and the second portion of the solution, and the method includes. providing the mean temperature of the heat exchanger by measuring the temperature of the heat exchange fluid. In a preferred embodiment, the method includes measuring the conductivity of the solution by diverting a portion of the solution from the decomposing step.
In accordance with the apparatus of the present invention, apparatus is provided for measuring the concentration of a decomposable compound in a solution comprising charging means for charging a buffer in gaseous form to the solution, a reactor for decomposing the decomposable compound whereby a reacted solution is formed, and measuring means for measuring the conductivities of the solution and the reacted solution whereby a differential conductivity can be calculated therefrom. In a preferred embodiment, the buffer in gaseous form comprises carbon dioxide. Preferably, the decomposable compound comprises urea, and the solution comprises bicarbonate ions. In another embodiment, the decomposing of the decomposable compound comprises catalytically reacting the solution, preferably reacting the solution with urease.
In accordance with one embodiment of the apparatus of the present invention, the apparatus is a silicon tube in contact with the solution whereby the carbon dioxide can be added to the solution by diffusion through the silicon tube.
In accordance with another embodiment of the apparatus of the present invention, the apparatus includes a bubble detector for detecting bubbles in the reacted solution.
In accordance with another embodiment of the apparatus of the present invention, the apparatus includes pressure increasing means for increasing the pressure of the solution in order to increase the solubility of the carbon dioxide in the solution.
In accordance with another embodiment of the apparatus of the present invention, the apparatus includes temperature decreasing means for decreasing the temperature of the solution in order to increase the solubility of the carbon dioxide in the solution during the measuring step.
In accordance with another embodiment of the apparatus of the present invention, the measuring means for measuring the conductivity of the solution and the reacted solution comprises a single measurement cell.
In accordance with another embodiment of the apparatus of the present invention, the apparatus comprises a first conduit path and a second conduit path, the first conduit path including the reactor, and wherein the measuring means for measuring the conductivities of the solution and the reacted solution comprises a first measuring means for measuring the conductivity of the solution and a second measuring means for measuring the conductivity of the reacted solution, the first measuring means be located in the second conduit path and the second measuring means being located in the first conduit path. In a preferred embodiment, the second conduit path is configured so that the flow of the solution through the first and second conduit paths to the first and second measurement cells takes approximately the same amount of time.
In accordance with another embodiment of the apparatus of the present invention, the heat exchanger is disposed for maintaining the temperatures of the solutions in the first and second conduit paths approximately equal.
An object of the present invention is to provide a method and a device for measuring the concentration of urea in a composite solution by heterogenous catalytic reaction of urea with urease in a reactor column for decomposing thereof, and measuring the differencial conductivity between reacted solution and unreacted solution for providing an indication of the concentration of urea in said solution. According to the invention, carbon dioxide is added to the solution, which comprises hydrogen carbonate ions, before the reaction in the reactor column. The carbon dioxide, together with the hydrogen carbonate ions, form a buffer maintaining the pH-value of the solution within predetermined limits. At the same time, the carbon dioxide contributes to making the relationship between the differential conductivity and the concentration of urea linear over a large range. The addition of carbon dioxide also results in each urea molecule being decomposed into four ions, each contributing to the increase in conductivity.
The carbon dioxide is added in the form of a gas, and preferably in such an amount that the solution is substantially saturated with carbon dioxide. In order to further increase the solubility of carbon dioxide gas in the solution, the pressure of the solution can be raised and/or the temperature of the solution can be lowered. In this way it is assured that a sufficient amount of carbon dioxide is dissolved in the solution for making the relationship linear over as large a range as possible.
The differential conductivity between reacted and unreacted solution can be measured by a single conductivity cell. The unreacted and reacted solutions can be switched to the single conductivity cell in sequence. In this way the two measurements are as equal as possible, independent of the construction of the conductivity cell.
It is also possible to measure the two conductivities with two separate conductivity cells, a first of which is positioned in a first branch including the reactor column and a second of which is positioned in a branch passing the reactor column. Since the measurement of conductivity is highly dependent on temperature, the measurement values must be corrected for temperature or the two different solutions must have the same temperature.
By placing the two conductivity cells in close proximity to each other and passing the two solutions through heat exchanging coils in a heat exchanger, the two solutions attain the same temperature.
Other features, properties and advantages appear from the appended claims.